The Silvio O. Conte Center at the University of Washington is designed with a specific goal of understanding how stress-exposure can exacerbate depressive symptoms and increase the risk of a depressive episode in vulnerable individuals. Clinical experience has established a strong interaction between a history of unregulated stress exposure and the risk of mood disorders, but how the stress- mediators produce enduring changes in brain function that result in depressive symptoms is not clear. Novel therapeutics based on new insights to these mechanisms have the potential to enhance stress-resilience in this vulnerable population. The research aims of this Center are designed to understand 1) how the dynorphins, which are released in response to repeated stress, cause aversive effects in mice that have been suggested to be responsible for a component of stress-induced dysphoria in humans; 2) how the serotonergic inputs from the dorsal raphe nucleus (DRN) that regulate the dopaminergic system in the ventral tegmental area (VTA) affect neuronal excitability and are changed by repeated social defeat stress exposure; 3) how stress exposure alters gene expression in the serotonergic neurons of the DRN; and 4) how repeated stress exposure alters the regulation by CRF of the dopamine release by VTA neurons projecting to the nucleus accumbens (NAc). These studies in mice will combined the use of transgenic Cre driver lines, conditional gene inactivation, optogenetics, and DREADD techniques to selectively regulate specific components of the DRN-> VTA -> NAc neuronal circuit known to be important in mood regulation. The studies will use behavioral, electrophysiological and fast-scan voltammetry techniques to measure the responses mediated by the different components of the circuit. Both male and female mice will be studied to identify sex-specific responses. The Center will include translational studies that attempt to link the mouse studies to stress responses in Women with treatment-resistant depression. A plausible hypothesis underlying this clinical study component is that the inflammatory mediators affecting gene expression in peripheral blood lymphocytes may also be acting as stress-mediators in brain. For example, both cytokines and dynorphins regulate the serotonin transporter function, and a link between their effects on neuronal circuits may suggest novel therapeutic approaches. The UW-Conte Center will support basic science and clinical research, as well as community Outreach and Training missions in a coordinated and synergistic mode.